Obesity is very prevalent among Pima Indians and represents the major risk factor for insulin resistance and the development of NIDDM. Over the past 10 years, our prospective studies have identified 4 metabolic parameters predicting body weight gain in Pimas: a low "relative" metabolic rate, a high respiratory quotient, a low spontaneous physical activity and insulin sensitivity. However, only part of the weight gain (30-40%) was explained by these factors. This clearly indicates that physical inactivity and/or excess energy intake contributes substantially to the development of obesity. One underlying mechanism of these metabolic predictors may be the activity of the sympathetic nervous system (SNS). Pima Indians have low SNS activity and unlike in Caucasians, this activity does not correlate with measures of energy expenditure. Using doubly labeled water, we have recently reported an inverse correlation between the level of physical activity and percent body fat. However, in more than 100 5-year old children, we have not been able to show that Pima Indians have lower physical activity than Caucasians. Therefore, excess food intake is most likely to play a major role in the etiology of obesity in this population. Recently we examined the possible role of glucocorticoids in the regulation of energy metabolism and food intake. Like in animals, acute glucocorticoid administration in humans is associated with decreased SNS activity and increased energy intake. Based on the evidence that obesity has a sizable genetic component, we undertook a genetic search first targeting candidate genes for obesity and now extended to the entire genome. Results can be summarized as follows: 1) markers flanking the gene TNF` at 6p21.3 showed a significant linkage to percent body fat. However, no polymorphism was detected in the 3 exons of the gene, 2) none of the single gene mutations described in rodent models of genetic obesity (db, ob, tub, fat, and A/y) has been found to be linked to obesity, 3 Markers on chromosome 11 are linked to percent body fat. Also markers on the short arm of chromosome 4 are linked to metabolic rate. These regions are being investigated for possible obesity candidate genes.